Pederin (1) and psymberin, also known as irciniastatin A, (2) are potent cytotoxins that contain a densely functionalized tetrahydropyran subunit and an N-acyl aminal linkage. These structural features are also found in the mycalamide/theopederin class of molecules, represented by theopederin D (3). Pederin was shown to be a mitotic poison in 1966, but further studies on the biological activity of this family of compounds were not reported until 19897 when the mycalamides were identified as potent cytotoxins that showed efficacy in vivo against leukemia and solid tumor models. This study also demonstrated that these compounds are protein synthesis inhibitors. Ogawara and co-workers showed that the mycalamides change ras-transformed cells to normal morphology, and correlated this activity to the inhibition of the synthesis of p21, a cyclin-dependent kinase inhibitor that regulates cell growth (Ogawara et al., Chem. Pharm. Bul. 1991, 39, 2152). The Kocienski group reported that pederin and the mycalamides induce necrosis is squamous carcinoma cells but not in fibroblasts (Richter et al., Anti-Cancer Dru Des. 1997, 12, 217). Further mechanistic work led to the conclusion that these compounds induce apoptosis in a number of cell lines by activating the c-Jun kinase (JNK) and the p31 mitogen-activated protein kinase (Lee et al., Cancer Sci. 2005, 96, 357). Usui and co-workers showed that psymberin induces a similar JNK activation, that the activation is a response to the accumulation of reactive oxygen species in the mitochondria, and that apoptosis is at least partially induced by caspase-8 (Chinen et al, Toxicol. Lett. 2010, 199, 341). Ribosome binding was demonstrated by the displacement of radiolabeled tedanolide from the 60S subunit by pederin, and by the crystal structure of mycalamide A in the ribosomal binding site for the CCA end of tRNAs that occupy the E-site. The interesting biological activity and unique structures of these compounds coupled with their scarcity from natural sources has resulted in a number of total, formal, and partial syntheses of pederin, the mycalamides, and psymberin.